Expression of homologous RND efflux pump genes is dependent upon AcrB expression: implications for efflux and virulence inhibitor design

Blair, Jessica M A; Smith, Helen; Ricci, Vito; Lawler, Amelia J.; Thompson, Louisa J.; Piddock, Laura J. V.

doi:10.1093/jac/dku380

Cited by 82 publications

(81 citation statements)

References 52 publications

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“…A recent study also showed that the expression level of the acrB, acrD, and/or acrF gene was increased when one or multiple acr genes were deleted (629), and this observation was similar to the situation found among the Mex pump genes of P. aeruginosa (628). However, the compensatory acr expression level changes appeared to have only a minimal impact on the drug susceptibility phenotype (except some aminoglycosides) (629).…”

Section: Salmonella Efflux Pumpsmentioning

confidence: 55%

“…In B. thailandensis, multidrug-resistant mutants selected by doxycycline overproduced AmrAB-OprA and BpeEF-OprC. When either of these pumps was inactivated, a third pump, BpeAB-OprB, was hyperexpressed, indicating the interplay among the three RND pumps (627), similar to those observed in P. aeruginosa (628) and Salmonella (629). Interestingly, an antagonistic effect between PA␤N (at 50 and 200 g/ml) and aminoglycosides/␤-lactams was observed, and the speculation was that PA␤N might have induced the overproduction of the AmrAB-OprA and BpeAB-OprB pumps (627).…”

Section: Burkholderia Sppmentioning

confidence: 76%

“…However, interpretation of these results, based mostly on the properties of deletion mutants of acrB and its homologs, needs some caution because such deletions are known to result in changes in the expressions of the other remaining pumps. For instance, the deletion of acrB in S. enterica serovar Typhimurium results in the overproduction of AcrD and AcrF (629,771). The mechanism of this regulatory response is still unclear, but it may be related to the function of AcrB (and possibly other constitutively expressed RND pumps in other species) in removing toxic intermediates of metabolism, first proposed by Helling et al (901) and more recently developed by Rosner and Martin (762,902).…”

Section: Involvement Of Mutlidrug Efflux Pumps In Other Functionsmentioning

confidence: 99%

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The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

2015

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SUMMARY The global emergence of multidrug-resistant Gram-negative bacteria is a growing threat to antibiotic therapy. The chromosomally encoded drug efflux mechanisms that are ubiquitous in these bacteria greatly contribute to antibiotic resistance and present a major challenge for antibiotic development. Multidrug pumps, particularly those represented by the clinically relevant AcrAB-TolC and Mex pumps of the resistance-nodulation-division (RND) superfamily, not only mediate intrinsic and acquired multidrug resistance (MDR) but also are involved in other functions, including the bacterial stress response and pathogenicity. Additionally, efflux pumps interact synergistically with other resistance mechanisms (e.g., with the outer membrane permeability barrier) to increase resistance levels. Since the discovery of RND pumps in the early 1990s, remarkable scientific and technological advances have allowed for an in-depth understanding of the structural and biochemical basis, substrate profiles, molecular regulation, and inhibition of MDR pumps. However, the development of clinically useful efflux pump inhibitors and/or new antibiotics that can bypass pump effects continues to be a challenge. Plasmid-borne efflux pump genes (including those for RND pumps) have increasingly been identified. This article highlights the recent progress obtained for organisms of clinical significance, together with methodological considerations for the characterization of MDR pumps.

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Section: Salmonella Efflux Pumpsmentioning

confidence: 55%

Section: Burkholderia Sppmentioning

confidence: 76%

Section: Involvement Of Mutlidrug Efflux Pumps In Other Functionsmentioning

confidence: 99%

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The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

2015

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“…In Gram-negative bacteria, AcrR regulators control expression of efflux pumps belonging to the AcrB family, which are often encoded by divergently transcribed genes, as with acrR-acrABC in E. coli (40) and the orthologous mtrR-mtrCDE arrangement in Neisseria gonorrhoeae (41). Similarly, farE is divergently transcribed from farR and encodes an 822-amino-acid protein that is annotated as a drug exporter of the resistance-nodulation-division (RND) superfamily (30), to which AcrB and orthologous efflux pumps are also assigned (42). Genome annotation also assigns FarE to the MMPL (mycobacterial membrane proteins, large) family of proteins, on the basis of homology to large membrane proteins of Mycobacterium tuberculosis that transport mycolic acids to the cell surface (43).…”

Section: Resultsmentioning

confidence: 99%

Inducible Expression of a Resistance-Nodulation-Division-Type Efflux Pump in Staphylococcus aureus Provides Resistance to Linoleic and Arachidonic Acids

et al. 2015

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Although Staphylococcus aureus is exposed to antimicrobial fatty acids on the skin, in nasal secretions, and in abscesses, a specific mechanism of inducible resistance to this important facet of innate immunity has not been identified. Here, we have sequenced the genome of S. aureus USA300 variants selected for their ability to grow at an elevated concentration of linoleic acid. The fatty acid-resistant clone FAR7 had a single nucleotide polymorphism resulting in an H 121 Y substitution in an uncharacterized transcriptional regulator belonging to the AcrR family, which was divergently transcribed from a gene encoding a member of the resistance-nodulation-division superfamily of multidrug efflux pumps. We named these genes farR and farE, for regulator and effector of fatty acid resistance, respectively. Several lines of evidence indicated that FarE promotes efflux of antimicrobial fatty acids and is regulated by FarR. First, expression of farE was strongly induced by arachidonic and linoleic acids in an farRdependent manner. Second, an H 121 Y substitution in FarR resulted in increased expression of farE and was alone sufficient to promote increased resistance of S. aureus to linoleic acid. Third, inactivation of farE resulted in a significant reduction in the inducible resistance of S. aureus to the bactericidal activity of 100 M linoleic acid, increased accumulation of [ 14 C]linoleic acid by growing cells, and severely impaired growth in the presence of nonbactericidal concentrations of linoleic acid. Cumulatively, these findings represent the first description of a specific mechanism of inducible resistance to antimicrobial fatty acids in a Gram-positive pathogen. IMPORTANCEStaphylococcus aureus colonizes approximately 25% of humans and is a leading cause of human infectious morbidity and mortality. To persist on human hosts, S. aureus must have intrinsic defense mechanisms to cope with antimicrobial fatty acids, which comprise an important component of human innate defense mechanisms. We have identified a novel pair of genes, farR and farE, that constitute a dedicated regulator and effector of S. aureus resistance to linoleic and arachidonic acids, which are major fatty acids in human membrane phospholipid. Expression of farE, which encodes an efflux pump, is induced in an farRdependent mechanism, in response to these antimicrobial fatty acids that would be encountered in a tissue abscess. Staphylococcus aureus has a dichotomous relation with human hosts, being able to establish an asymptomatic commensal relationship, but is also historically known as a leading cause of human infectious morbidity and mortality. Significantly, death attributed to S. aureus in the United States is now comparable to mortality rates for AIDS, tuberculosis, and viral hepatitis (1-3). Not surprisingly, therefore, S. aureus has been the subject of intensive research on mechanisms of pathogenesis and acquisition and transfer of antibiotic resistance and of efforts to identify potential vaccine antigens (4-6). Until the late ...

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“…The role of RND efflux pumps is not limited to the multidrug resistance (MDR) phenotype, since some of them have been shown to be required for virulence traits of different Gram-negative pathogens (11,12). This explains why AcrB is considered the main clinically relevant RND system and constitutes a privileged target for the development of efflux pump inhibitor (EPI) molecules that could be used to treat infections (13)(14)(15). In Enterobacteriaceae, numerous other genes encoding RND pumps are present in the genomes, but their roles have been poorly investigated so far.…”

mentioning

confidence: 99%

Landscape of Resistance-Nodulation-Cell Division (RND)-Type Efflux Pumps in Enterobacter cloacae Complex

Guérin

Lallement

Isnard

et al. 2016

Antimicrob Agents Chemother

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cIn Gram-negative bacteria, the active efflux is an important mechanism of antimicrobial resistance, but little is known about the Enterobacter cloacae complex (ECC). It is mediated primarily by pumps belonging to the RND (resistance-nodulation-cell division) family, and only AcrB, part of the AcrAB-TolC tripartite system, was characterized in ECC. However, detailed genome sequence analysis of the strain E. cloacae subsp. cloacae ATCC 13047 revealed to us that 10 other genes putatively coded for RNDtype transporters. We then characterized the role of all of these candidates by construction of corresponding deletion mutants, which were tested for their antimicrobial susceptibility to 36 compounds, their virulence in the invertebrate Galleria mellonella model of infection, and their ability to form biofilm. Only the ⌬acrB mutant displayed significantly different phenotypes compared to that of the wild-type strain: 4-to 32-fold decrease of MICs of several antibiotics, antiseptics, and dyes, increased production of biofilm, and attenuated virulence in G. mellonella. In order to identify specific substrates of each pump, we individually expressed in trans all operons containing an RND pump-encoding gene into the ⌬acrB hypersusceptible strain. We showed that three other RND-type efflux systems (ECL_00053-00055, ECL_01758-01759, and ECL_02124-02125) were able to partially restore the wild-type phenotype and to superadd to and even enlarge the broad range of antimicrobial resistance. This is the first global study assessing the role of all RND efflux pumps chromosomally encoded by the ECC, which confirms the major role of AcrB in both pathogenicity and resistance and the potential involvement of other RND-type members in acquired resistance.

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Expression of homologous RND efflux pump genes is dependent upon AcrB expression: implications for efflux and virulence inhibitor design

Cited by 82 publications

References 52 publications

The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

Inducible Expression of a Resistance-Nodulation-Division-Type Efflux Pump in Staphylococcus aureus Provides Resistance to Linoleic and Arachidonic Acids

Landscape of Resistance-Nodulation-Cell Division (RND)-Type Efflux Pumps in Enterobacter cloacae Complex

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